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R E S E A R C H Open Access

Gram-negative bacteremia induces greater

magnitude of inflammatory response than

Gram-positive bacteremia

Ryuzo Abe*, Shigeto Oda, Tomohito Sadahiro, Masataka Nakamura, Yo Hirayama, Yoshihisa Tateishi,

Koichiro Shinozaki, Hiroyuki Hirasawa

Abstract

Introduction: Bacteremia is recognized as a critical condition that influences the outcome of sepsis Although large-scale surveillance studies of bacterial species causing bacteremia have been published, the pathophysiological differences in bacteremias with different causative bacterial species remain unclear The objective of the present study is to investigate the differences in pathophysiology and the clinical course of bacteremia caused by different bacterial species

Methods: We reviewed the medical records of all consecutive patients admitted to the general intensive care unit (ICU) of a university teaching hospital during the eight-year period since introduction of a rapid assay for

interleukin (IL)-6 blood level to routine ICU practice in May 2000 White blood cell count, C-reactive protein (CRP), IL-6 blood level, and clinical course were compared among different pathogenic bacterial species

Results: The 259 eligible patients, as well as 515 eligible culture-positive blood samples collected from them, were included in this study CRP, IL-6 blood level, and mortality were significantly higher in the septic shock group (n = 57) than in the sepsis group (n = 127) (P < 0.001) The 515 eligible culture-positive blood samples harbored a total

of 593 isolates of microorganisms (positive, 407; negative, 176; fungi, 10) The incidence of Gram-negative bacteremia was significantly higher in the septic shock group than in the sepsis group (P < 0.001) and in the severe sepsis group (n = 75, P < 0.01) CRP and IL-6 blood level were significantly higher in Gram-negative bacteremia (n = 176) than in Gram-positive bacteremia (n = 407) (P < 0.001, <0.0005, respectively)

Conclusions: The incidence of Gram-negative bacteremia was significantly higher in bacteremic ICU patients with septic shock than in those with sepsis or severe sepsis Furthermore, CRP and IL-6 levels were significantly higher in Gram-negative bacteremia than in Gram-positive bacteremia These findings suggest that differences in host

responses and virulence mechanisms of different pathogenic microorganisms should be considered in treatment of bacteremic patients, and that new countermeasures beyond conventional antimicrobial medications are urgently needed

Introduction

Despite recent advances in critical care medicine, the

mortality of sepsis in ICU remains high [1,2] Among

various infections underlying sepsis, bacteremia is

recog-nized as a critical condition that influences the outcome

of sepsis [3,4], and is reportedly associated with an

attri-butable mortality of approximately 35% [5] While the

larger part of pathogens in sepsis-inducing infections was previously Gram-negative bacteria, currently the lar-ger part of pathogens identified in sepsis is Gram-posi-tive bacteria [1,6], with an increasing proportion of multi-resistant bacteria [7] Although large-scale surveil-lance studies of bacterial species causing bacteremia have been published [7,8], the pathophysiological differ-ences in bacteremias with different causative bacterial species remain unclear

* Correspondence: ryuzo@pf6.so-net.ne.jp

Department of Emergency and Critical Care Medicine, Chiba University

Graduate School of Medicine, 1-8-1 Inohana Chuo, Chiba, 260-8677, Japan

© 2010 Abe et al.; licensee BioMed Central Ltd This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in

Since 2000, we have used a rapid assay system for

interleukin (IL)-6 blood level, aiming at real-time

assess-ment of the magnitude of inflammatory response to

facilitate prompt determination of disease severity and

therapeutic effects [9] The objective of the present

study was to investigate differences in the

pathophysio-logy and clinical course of bacteremia caused by

differ-ent bacterial species by cross-check review of laboratory

findings and the clinical record with pathogenic

micro-bial species in bacteremic patients who were admitted

to the ICU during the eight years since introduction of

the rapid IL-6 assay to routine ICU practice

Materials and methods

Study population

We reviewed the medical records of all consecutive

patients admitted to the general ICU of a university

teaching hospital during the period from May 2000 to

October 2008 Patients with one or more blood samples

processed for culture were enrolled in the study Among

culture-positive patients, those fulfilling diagnostic

cri-teria for sepsis described below and undergoing blood

sampling for measurement of white blood cell count

(WBC), C-reactive protein (CRP), and IL-6

concomi-tantly with collection of blood culture samples were

finally included in the extensive review described below

(see Figure 1) Informed consent for blood sampling as

a part of daily practice and later use of the data for aca-demic purpose was obtained from all patients or their family members when the patients were admitted to the ICU The study was approved by the institutional ethics committee

For the diagnosis of sepsis, the criteria of the Ameri-can College of Chest Physicians/Society of Critical Care Medicine Consensus Conference were applied [10] The criteria were as follows Fulfillment of both of the fol-lowing, (1) and (2), was required: (1) The presence of systemic inflammatory response syndrome (manifested

by two or more of the following criteria: fever (tempera-ture above 38°C) or hypothermia (tempera(tempera-ture below 35.5°C), tachycardia (more than 90 beats per minute), tachypnea (more than 20 breaths per minute), or hypo-capnia (PaCO2 of less than 32 torr), and leukocytosis or leukopenia (white blood cell count of more than 12,000/

mm3or less than 4,000/mm3, respectively)); (2) a docu-mented source of infection

Among patients meeting the diagnostic criteria for sepsis described above, those also meeting at least one

of the following criteria for organ failure were classified

in the severe sepsis group: hypoxemia (PaO2/FiO2 < 300), acute oliguria (urine output <0.5 mL/kg/hr persist-ing two hours or longer), serum creatinine >2.0 mg/dL, coagulation disorder (PT-INR > 1.5), thrombocytopenia (PLT < 100,000/mL), hyperbilirubinemia (T-Bil > 2.0

Figure 1 Selection of eligible patients and blood culture samples Patients were admitted to the ICU between May 2000 and October 2008 SIRS: systemic inflammatory response syndrome.

mg/dL), and hyperlactatemia (blood lactate >18 mg/dL).

Of those in the severe sepsis group, those with a systolic

pressure of 90 mmHg or lower that persisted despite

appropriate fluid resuscitation and required a

vasopres-sor were classified in the septic shock group The

remaining patients classified in neither thesevere sepsis

nor theseptic shock group comprised the sepsis group

Patients with hematological malignancies and

autoim-mune disorders who needed treatment of

immunosup-pressive drug therapy were excluded from the present

study Immunosuppressive drugs include predonisolone,

methylpredonisolone, cyclophosphamide, cyclosporine,

doxorubicin, vincristine, methotrexate, rituximab and

FK506 Patients with positive blood culture but not

meeting the diagnostic criteria for sepsis were also

excluded from the study to eliminate the possibility of

samples false-positive as a result of contamination

Sam-ples collected through central venous catheter and

sam-ples collected through peripheral vein puncture were

excluded from the study to eliminate the possible

var-iance of blood levels of biomarkers between arterial

blood and venous blood Patients whose blood culture

showed skin indigenous bacteria in only one of the

duplicate samples were also excluded

Coagulase-nega-tive Staphylococcus, Corynebacterium species,

Micro-coccus species and Propionibacterium species were

defined as skin indigenous bacteria

Blood culture

Blood culture samples were collected from arterial

catheters by ICU staff doctors Before taking blood

sam-ples, catheter ports or stopcocks were disinfected with

povidone-iodone swab and 70% isopropyl alcohol swab

A 10 mL blood sample was divided evenly into

anaero-bic and aeroanaero-bic culture bottles at the bedside Blood

samples were processed using a BACTEC 9240

auto-mated blood culture system in combination with both

standard aerobic and anaerobic media available from the

instrument manufacturer (Becton Dickinson Diagnostic

Instrument Systems, Paramus, NJ, USA) Bacteria were

identified using standard methods Two distinct episodes

of bloodstream infection were recorded for a patient,

regardless of bacterial species detected, if at least six

days had elapsed between the two positive blood

cul-tures, provided appropriate therapy had been

implemen-ted and significant clinical improvement had been

obtained between the two episodes

Cytokine blood levels

Blood samples were obtained from arterial catheter

simultaneously with collection of culture samples in all

the patients studied IL-6 blood levels were measured

with a chemiluminescence enzyme immunoassay using a

rapid measurement system (Human IL-6 CLEIA,

Fujirebio, Tokyo, Japan) The duration of processing for IL-6 measurement was approximately 30 minutes [9] Grouping of patients and blood culture samples First, the three patient groups divided according to severity of sepsis (sepsis, severe sepsis, and septic shock) were compared for white blood count, CRP, and IL-6 blood level as well as mortality

Culture-positive blood samples were divided into two groups, positive (GP) sample group and Gram-negative (GN) sample group, according to the bacterial species detected When both positive and Gram-negative bacteria were detected in one blood culture sample, the sample was included in both the GP and

GN sample groups WBC, CRP, and IL-6 blood levels were compared between these two sample groups Finally, all bacteremic patients were divided into three groups according to bacterial species detected during the clinical course: GP patients’ group, one or more Gram-positive species detected; GN patients’ group, one

or more Gram-negative species detected; and GP/GN patients’ group, both Gram-positive and Gram-negative species detected These three patient groups were com-pared for severity and clinical outcome Severity of ill-ness was assessed by calculating Acute Physiology and Chronic Health Evaluation (APACHE)-II score [11] and Sequential Organ Failure Assessment (SOFA) score [12] Statistical analysis

Comparisons of variables among groups were performed with the unpaired Student’s t-test, except for sex, mor-tality, and positivity for Gram-positive and Gram-nega-tive bacteria, which were compared with the chi-square test Statistical significance was defined as P < 0.05 Sta-tistical analyses were performed with the SPSS 13.0 J for Windows software package (SPSS Inc, Chicago, IL, USA)

Results

Between May 2000 and October 2008, 4,092 patients were admitted to the ICU, and 2,528 of them underwent blood culture tests Positive blood culture was confirmed for 743 of 4,191 samples submitted After eliminating those meeting the exclusion criteria the remaining 515 culture-positive samples were included in the present study These samples were collected from 259 patients and harbored a total of 593 microorganism isolates (Figure 1)

The 259 eligible patients included 127 patients in the sepsis group, 75 patients in the severe sepsis group, and

57 patients in the septic shock group Table 1 sum-marizes background characteristics, WBC, CRP, and IL-6 (measured concomitantly with collection of culture-positive blood samples) as well as causative

microorganisms and mortality in the three patient

groups Results demonstrated that CRP level was

signifi-cantly higher in the septic shock group than in the

sep-sis group The IL-6 blood level was significantly higher

in the septic shock group than in the sepsis and in the

severe sepsis groups Furthermore, mortality in the

sep-tic shock group was significantly higher than that in the

sepsis group The incidence of Gram-positive bacteremia

in the septic shock group was significantly lower than

those in the two other patient groups, while the

inci-dence of Gram-negative bacteremia was significantly

higher in the septic shock group than in any other

group The incidence of bacteremia caused by both

Gram-positive and Gram-negative bacteria was

signifi-cantly higher in the septic shock group than in the

sep-sis group; this was also the case for the incidence of

bacteremia caused by multiple organisms

Table 2 compares patient characteristics, severity

scores, length of ICU stay and mortality among GP

patients’ group (n = 168), GN patients’ group (n = 70)

and GP/GN patients’ group (n = 15) APACHE II score

was significantly higher in the GN patients’ group than

in GP patients’ group, while no significant differences

were noted between any pair of groups examined

The 515 eligible culture-positive blood samples

har-bored a total of 593 isolates of microorganisms,

including 407 isolates of Gram-positive bacteria, 176 isolates of Gram-negative bacteria, and 10 isolates of fungi Two or more different microbial species were concomitantly detected in 60 blood culture samples As demonstrated in Figure 2, both CRP and IL-6 blood level were significantly higher in the GN sample group

Discussion

We reviewed medical records of septic patients admitted

to the ICU and being positive on blood culture during the last eight years for comparison of background char-acteristics, WBC, CRP, and IL-6 as well as causative microorganisms and clinical outcome When eligible patients were classified into three groups by severity of sepsis, the prevalence of Gram-negative bacteremia, pre-valence of bacteremia caused by both Gram-positive and Gram-negative bacteria, and IL-6 blood level were sig-nificantly higher in the septic shock group than in either

of the other two groups (Table 1) When episodes of bacteremia caused by Gram-positive and Gram-negative bacteria were compared, CRP and IL-6 blood level were found to be significantly higher in Gram-negative bac-teremia (Figure 2) Notably, the sample size in the pre-sent study (176 and 407 for episodes of Gram-negative and Gram-positive bacteremia, respectively) is larger than that in any other similar study published to date

Table 1 Patients’ characteristics, white blood cell count, C-reactive protein and interleukin-6 blood level and mortality

Total

N = 259

Sepsis

N = 127

Severe sepsis

N = 75

Septic shock

N = 57 P value Age yrs, mean (SD) 58.1

(18.6)

54.7 (18.6)

61.0 (17.3)

61.7 (19.2)

<0.05a,b Male, n (%) 180

(69.5)

88 (69.3)

55 (73.3)

37 (64.9)

ns WBC (*103/mm3), mean (SD) 14.0

(9.5)

14.1 (8.1)

15.2 (10.9)

12.8 (11.0)

ns CRP (mg/dL), mean (SD) 11.8

(9.1)

10.0 (8.5)

11.4 (9.3)

15.6 (9.5)

<0.001b IL-6 (pg/mL), mean (SD) 33,543

(136,974)

8,398 (47,705)

8,176 (37,975)

118,435 (264,819)

<0.001 b , c

Gram positive bacteremia, n (%) 168

(64.9)

92 (72.4)

51 (68.0)

25 (43.9)

<0.0005d

<0.01 e

Gram negative bacteremia, n (%) 70

(27.0)

28 (22.0)

17 (22.7)

25 (43.9)

<0.005 d

<0.01e Both of Gram positive and negative bacteremia*, n (%) 15

(5.8)

4 (3.1)

4 (5.3)

7 (12.3)

<0.05 d

Fungemia*, n (%) 7

(2.7)

3 (2.3)

3 (4.0)

1 (1.8)

ns Bacteremia caused by multiple organisms, n (%) 16

(6.2)

4 (3.1)

4 (5.3)

8 (14.0)

<0.01 d

Length of ICU stay (day), mean (SD) 19.4

(21.7)

20.6 (22.4)

17.4 (17.7)

19.5 (24.9)

ns Mortality (%) 31.3 20.5 36.0 49.1 <0.001d

WBC, white blood cell count; CRP, C-reactive protein; IL-6, interleukin-6 *One case overlapping because Gram-positive bacteria and fungi were detected.aWith unpaired Student ’s T test, between sepsis group and severe sepsis group b

With unpaired Student ’s T test, between sepsis group and septic shock group c

With unpaired Student’s T test, between severe sepsis group and septic shock group d

With Chi square test, between sepsis group and septic shock group e

With Chi square test, between severe sepsis group and septic shock group.

Although differences in the magnitude of insult

depending on the type of pathogen, that is, the type of

pathogen-associated molecular patterns (PAMPs), have

been already recognized [13], few studies have examined

this difference quantitatively While Fisher et al [14]

previously reported that plasma IL-6 levels were

signifi-cantly higher in patients with Gram-negative bacteremia

(n = 17) than in those with Gram-positive bacteremia (n

= 12), the present study is, to the best of our knowledge,

the first demonstration of such differences in response

to bacterial bloodstream infection among different

cau-sative bacterial species in a sufficiently large study

popu-lation Our finding that CRP and IL-6 blood level were

significantly higher in Gram-negative bacteremia than in

Gram-positive bacteremia suggests that different types

of PAMPs may induce different types and magnitudes of response Since IL-6 is not only an index of response to invasion but also a typical alarmin [15], IL-6 per se may induce further exacerbation of pathophysiological condition

The magnitude of biological response to insult has been believed to be determined by the magnitude of insult as well as host predisposition This concept has been schematized in the recently proposed PIRO model (Predisposition, Insult, Response, and Organ dysfunc-tion) [16] When the PIRO model is applied to cases of sepsis, the nature of insult can be considered infection, with the site, type, and extent of infection significantly

Table 2 Patients’ characteristics, severity scores, length of ICU stay and mortality in GP, GN, GP/GN groups

GP patients ’ group (n = 168) GN patients’ group (n = 70) GP/GN patients’ group (n = 15) P value Age (yrs), mean (SD) 56.2 (18.9) 61.7 (17.2) 60.3 (21.0) ns Male, n (%) 118 (70.2) 48 (68.6) 9 (60.0) ns APACHE II, mean (SD) 21.8 (9.5) 24.6 (7.4) 23.6 (10.7) <0.05 a

SOFA, mean (SD) 9.53 (5.0) 10.71 (4.4) 11.66 (6.0) ns Length of ICU stay (days), mean (SD) 18.7 (15.8) 20.5 (29.6) 16.2 (17.5) ns Mortality, (%) 28.0 40.0 33.3 ns

GP, Gram-positive; GN, Gram-negative; GP/GN, Gram-positive and Gram-negative; APACHE-II, Acute Physiology and Chronic Health Evaluation-II; SOFA, Sequential Organ Failure Assessment a

With Mann-Whitney ’s U-test, between GP patients’ group and GN patients’ group.

Figure 2 WBC, CRP and IL-6 levels in GP sample group and GN sample group Blood samples used for measurement of laboratory parameters were collected concomitantly with sampling for blood culture *P value calculated by Student ’s t-test CRP, C-reactive protein; GP, gram-positive sample group; GN, gram-negative sample group; IL-6, interleukin-6; WBC, white blood cell count.

impacting prognosis [16] Furthermore, it is known that

the mechanisms of bacterial virulence vary depending

on bacterial species and strain [17] For example, S

aur-eus produces protein A, which is a ligand for tumor

necrosis factor (TNF) receptor-1 and induces a response

identical to that caused by TNF-a stimulation [18] In

addition, some Group B Streptococcus strains produce

C5a peptidase to inhibit activation of the complement

system [19] Differences in mechanisms of bacterial

viru-lence result in differences in host response, that is,

dif-ferences in the extent of activation of various signaling

cascades and stimulation/inhibition of host cell

apopto-sis [17,20], leading to influence prognoapopto-sis

Earlier initiation of appropriate antimicrobial therapy

is clearly crucial in the treatment of sepsis [21] On the

other hand, though no countermeasures taking

differ-ences in the mechanisms of bacterial virulence into

account are currently available in clinical practice,

anti-microbial therapy beyond conventional antianti-microbial

medications is urgently needed Some recent studies

suggest future possibilities for such therapies For

exam-ple, inhibition of quorum-sensing regulated genes of

Pseudomonas aeruginosa by synthetic furanones

improved survival in a mouse model of pneumonia [22]

Such virulence-targeting antimicrobial therapies are

expected to provide new options for the treatment of

sepsis in ICU [23]

PAMPs from Gram-negative and Gram-positive

bac-teria are known to act as ligands for mutually different

pattern recognition receptors including Toll-like

recep-tors [24], and the molecular mechanisms underlying the

differential responses to infection with Gram-negative

and Gram-positive bacteria have been investigated [25]

However, the effects of differences in the molecular

mechanisms of response to invasion of Gram-negative

and Gram-positive bacteria on the clinical course and

prognosis of sepsis require further clarification In

parti-cular, IL-6 and CRP are known to be relatively

non-spe-cific biomarkers, compared with more validated

biomarkers for sepsis, such as procalcitonin and

trigger-ing receptors expressed on myeloid cell (TREM)-1 The

differences of blood levels of such non-specific

biomar-kers warrant further characterization at the molucular

level of the differences in virulence mechanisms between

Gram-negative and Gram-positive bacteremia

The present study has the following limitations First,

it was a retrospective study Second, it was a

single-cen-ter study in which it is difficult to rule out the

possibi-lity of bias in bacterial species identified and in patients’

characteristics In particular, the high percentage of

male patients (69.5%, Table 1) implies such possibility of

bias, even though this male-female ratio was consistent

with that of all patients admitted to our ICU during

eight years (63.3%, n = 4,092, male 2,590, female 1,502) However, the same male predominance in ICU popula-tion was also noticed before, even though the reason for this male predominance is unknown [26] Length of ICU stay also might suggest the existence of bias, since the three groups divided by severity of sepsis did not show differences in length of stay In addition to that, since patients in the septic shock group and the severe sepsis group were significantly older than the sepsis group patients, those differences might affect the magni-tude of inflammatory reactions and outcomes Regarding the severity of Gram-positive and Gram-negative patient groups, SOFA score did not demonstrate the significant difference between groups, though APACHE II score did (Table 2) This result suggests that the number of patients might not be enough to reach the conclusion Furthermore, because molecular mechanism of virulence underlying the present findings is not yet clarified, these results cannot be directly translated into practical man-agement Nevertheless, the present study has the merit

of having demonstrated differences in blood cytokine levels in bacteremia caused by different bacterial species

in a study population larger than that of any of the other similar studies

Conclusions

Patients admitted to the ICU with bacteremia were clas-sified according to severity of sepsis for comparison of pathogenic microorganisms and blood levels of inflam-matory biomarkers The incidence of Gram-negative bacteria and CRP and IL-6 blood level were significantly higher in the septic shock group than in the sepsis and severe sepsis groups Furthermore, CRP and IL-6 blood level measured concomitantly with sampling for blood culture were significantly higher in Gram-negative bac-teremia than in Gram-positive bacbac-teremia These find-ings suggest that differences in host responses and virulence mechanisms of different pathogenic microor-ganisms should be considered in treatment of bactere-mic patients, and that new countermeasures beyond conventional antimicrobial medications are urgently needed

Key messages

• CRP and IL-6 blood level were significantly higher in Gram-negative bacteremia than in Gram-positive bacteremia

• The incidence of Gram-negative bacteremia was sig-nificantly higher in bacteremic ICU patients with septic shock than in those with sepsis or severe sepsis

• Characterization at the molecular level of the differ-ences in virulence mechanisms between Gram-negative and Gram-positive bacteria is required

APACHE-II: Acute Physiology and Chronic Health Evaluation-II; CRP: C-reactive

protein; IL-6: interleukin-6; PAMPs: pathogen-associated molecular patterns;

SOFA: Sequential Organ Failure Assessment; WBC: white blood cell

Authors ’ contributions

RA designed the study and interpreted the results OS and HH made critical

revision of the manuscript for important intellectual content TS, MN, YH,

and YT drafted the manuscript KS participated in the analysis of data and

performed the statistical analysis All authors read and approved the final

manuscript.

Authors ’ information

RA is Assistant Professor, Department of Emergency and Critical Care

Medicine, Chiba University Hospital and a Board Certified Member of the

Japanese Society of Intensive Care Medicine OS is Professor and Chairman,

Department of Emergency and Critical Care Medicine, Chiba University

Graduate School of Medicine, and a Board Certified Member of the Japanese

Society of Intensive Care Medicine HH is Professor Emeritus and Former

Chairman, Department of Emergency and Critical Care Medicine, Chiba

University Graduate School of Medicine, and is Immediate Past President of

the Japanese Society of Intensive Care Medicine.

Competing interests

The authors declare that they have no competing interests.

Received: 15 December 2009 Revised: 1 February 2010

Accepted: 4 March 2010 Published: 4 March 2010

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doi:10.1186/cc8898 Cite this article as: Abe et al.: Gram-negative bacteremia induces greater magnitude of inflammatory response than Gram-positive bacteremia Critical Care 2010 14:R27.

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